Imaging Stimulant and Non Stimulant Treatments for ADHD: A Network Based Approach
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Purpose
The growing number of medications used to treat attention-deficit/hyperactivity disorder (ADHD) raises important questions about whether different medications have similar or different therapeutic mechanisms of action. We have recently shown that the stimulant methylphenidate (MPH) and the non-stimulant atomoxetine (ATX) produce clinical improvement via a common mechanism in motor cortex, and distinct actions in frontostriatal and midline cingulate-precuneus regions. These exciting findings offer a window into the common and unique neurophysiological mechanisms of response to stimulant and non-stimulant treatments. However, the interpretation and clinical utility of these results would be greatly enhanced by in-depth investigation of the impact of the two treatments on relevant neural networks, and analyses which evaluate whether improvement is achieved via normalization or other adaptive changes in brain function.
| Condition | Intervention | Phase |
|---|---|---|
|
Attention Deficit Hyperactivity Disorder ADHD |
Other: fMRI scans Drug: Atomoxetine arm Drug: Methylphenidate arm |
Phase 4 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Pharmacodynamics Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Treatment |
| Official Title: | Imaging Stimulant and Non Stimulant Treatments for ADHD: A Network Based Approach |
- Brain Activation [ Time Frame: Baseline and at 6 - 8 weeks ] [ Designated as safety issue: No ]
Comparison of brain activation at 6-8 weeks changed from baseline.
a) 'Task-positive' regions; b) 'Task-negative' regions; c) 'Task-positive' regions and 'task-negative' regions;d) Normalization of reduced connectivity; e) Compensatory increases in functional connectivity
- Go-Nogo [ Time Frame: Baseline and at 6-8 weeks ] [ Designated as safety issue: No ]Comparison of Go-Nogo at 6-8 weeks changed from baseline. Performance on a go-nogo task inside the scanner
- ADHD-RS [ Time Frame: up to 8 weeks ] [ Designated as safety issue: No ]behavioral symptoms of ADHD
| Estimated Enrollment: | 144 |
| Study Start Date: | October 2012 |
| Estimated Study Completion Date: | August 2017 |
| Estimated Primary Completion Date: | August 2017 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Placebo Comparator: fMRI scans
Control Group: will receive initial evaluation, and 2 fMRI (functional magnetic resonance imaging) scans each 6-8 weeks apart
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Other: fMRI scans
Control Group: will receive initial evaluation, and 2 fMRI scans each 6-8 weeks apart
|
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Experimental: Atomoxetine arm
These subjects will receive initial evaluation and baseline fMRI scan, flexible dose titration with atomoxetine for 6-8 weeks, and fMRI postscan.
|
Drug: Atomoxetine arm
These subjects will receive initial evaluation and baseline fMRI scan, flexible dose titration with atomoxetine prescribed at weekly visits for 6-8 weeks, and fMRI postscan.
Other Names:
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Experimental: Methylphenidate arm
subjects will receive initial evaluation, baseline fMRI scan, flexible dose titration with methylphenidate (Concerta) for 6-8 weeks, and fMRI scan post treatment.
|
Drug: Methylphenidate arm
Subjects will receive initial evaluation, baseline fMRI scan, flexible dose titration with methylphenidate for 6-8 weeks, and fMRI scan post treatment.
Other Names:
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Detailed Description:
The specific aims of this project are to use functional magnetic resonance imaging (fMRI) to determine the significance of activation changes over treatment related to clinical improvement, and the impact of treatment on neural connectivity within and between the anti-correlated frontostriatal 'task-positive' circuit and cingulate-precuneus 'task-negative' network. Our central hypotheses are that clinical improvement is associated with: (i) normalization of reduced connectivity of regions within the 'task-positive' network, with resultant increased inhibition of motor cortex, and (ii) normalization of low task-related connectivity in regions within the task-negative network for MPH and the 'task-positive' network for ATX.
This research proposes to test a model which posits a neurophysiological basis of mechanisms of response to stimulant and non-stimulant medications, and fits with our long term objectives of being able to match treatments to individual patients. Testing this model requires large samples of youth scanned using fMRI before and after treatment, and matched healthy controls also scanned twice. We will use an innovative network-based approach to study the effects of treatment, building on results from our current fMRI treatment study, and incorporating new theoretical approaches to understanding ADHD and its treatment.
Eligibility| Ages Eligible for Study: | 7 Years to 17 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | Yes |
Inclusion Criteria:
General inclusion criteria for subjects with ADHD and healthy controls are:
- aged 7-17 years;
- Wechsler Intelligence Scale for Children (WISC) scores ≥ 75;
- informed consent and assent to study participation.
Specific inclusion criteria for youth with ADHD are:
- diagnosis of ADHD, any subtype, determined by Kiddie Schedule for Affective Disorders and Schizophrenia for School-Aged Children-Present and Lifetime Versions (K-SADS-PL);
- ADHD Rating Scale-IV-Parent Version: Investigator Administered (ADHD-RSIV) total score ≥ 1.5 SD above age and gender means for subtype
- Clinical Global Impressions-ADHD-Severity (CGI-S) score > 4;
- ADHD must be the primary diagnosis and focus of treatment, and the treatments offered in the study must not be contraindicated for the comorbid disorder.
Exclusion Criteria:
General exclusion criteria are:
- history of head injury with loss of consciousness or any CNS disease that is likely to affect brain function;
- diagnosis of autism or pervasive developmental, psychotic, major mood, and Tourette's disorder;
- alcohol or drug abuse in the past 3 months or a positive urinary toxic screen on initial evaluation;
- use of psychotropic medication within 2 weeks of the study (8 weeks for fluoxetine);
- pre-existing medical or psychological condition which precludes being in the scanner (e.g., claustrophobia, morbid obesity);
- metal in the body that precludes scanning (e.g., braces, metal plate);
- positive urine pregnancy test.
Specific exclusion criteria for the treatment trial include:
- previous unsuccessful trial of MPH or ATX that was adequately dosed (≥ 1 mg/kg for MPH or 1.0 mg/kg for ATX) and of adequate duration (≥ 4 weeks);
- abnormal findings on physical exam, or vital signs
- pulse and blood pressure > 95% of age and gender mean;
- inability to swallow capsules;
- weight is < 20 kg or > 85 kg.
Specific exclusion criteria for control youth include:
- no past history or current diagnosis of any psychiatric disorder, determined by the K-SADS-PL interview;
- ADHD-RS-IV and CBCL scores for each symptom domain ≤ 1 SD of age and gender means.
Contacts and Locations| Contact: Beth Krone, Doctoral Candidate | 212-241-8012 | Beth.Krone@mssm.edu |
| Contact: Jeffrey Newcorn, MD | 212 659-8775 | Jeffrey.Newcorn@mssm.edu |
| United States, New York | |
| Icahn School of Medicine at Mount Sinai | Recruiting |
| New York, New York, United States, 10029 | |
| Principal Investigator: Jeffrey Newcorn, MD | |
| Principal Investigator: Kurt Schulz, PhD | |
| Principal Investigator: | Jeffrey Newcorn, MD | Icahn School of Medicine at Mount Sinai |
| Principal Investigator: | Kurt Schulz, PhD | Icahn School of Medicine at Mount Sinai |
More Information
No publications provided
| Responsible Party: | Jeffrey Newcorn, Director Division of Child and Adolescent Psychiatry, Associate Professor Psychiatry and Pediatrics, Medical Director Center for Excellence for ADHD and Related Disorders, Mount Sinai School of Medicine |
| ClinicalTrials.gov Identifier: | NCT01678209 History of Changes |
| Other Study ID Numbers: | GCO 11-0161 |
| Study First Received: | August 30, 2012 |
| Last Updated: | March 14, 2013 |
| Health Authority: | United States: Food and Drug Administration United States: Institutional Review Board |
Keywords provided by Mount Sinai School of Medicine:
|
Attention Deficit Hyperactivity Disorder Stimulant Non-stimulant Drug Methylphenidate Atomoxetine Strattera Concerta MACRO Medication Treatment |
Youth Adolescent Functional Magnetic Resonance Imaging Brain scan Imaging Response inhibition Inattentive Hyperactive Combined Medication Treatment Brain Imaging |
Additional relevant MeSH terms:
|
Attention Deficit Disorder with Hyperactivity Hyperkinesis Attention Deficit and Disruptive Behavior Disorders Mental Disorders Diagnosed in Childhood Mental Disorders Dyskinesias Neurologic Manifestations Nervous System Diseases Signs and Symptoms Central Nervous System Stimulants Methylphenidate Atomoxetine |
Physiological Effects of Drugs Pharmacologic Actions Central Nervous System Agents Therapeutic Uses Dopamine Uptake Inhibitors Dopamine Agents Neurotransmitter Agents Molecular Mechanisms of Pharmacological Action Neurotransmitter Uptake Inhibitors Adrenergic Uptake Inhibitors Adrenergic Agents |
ClinicalTrials.gov processed this record on May 19, 2013